Differential Regulation of Dynein and Kinesin Motor Proteins by Tau

Abstract

Dynein and kinesin motor proteins transport cellular cargos toward opposite ends of microtubule tracks. In neurons, microtubules are abundantly decorated with microtubule-associated proteins (MAPs) such as tau. Motor proteins thus encounter MAPs frequently along their path. To determine the effects of tau on dynein and kinesin motility, we conducted single molecule studies of motor proteins moving along tau-decorated microtubules. Dynein tended to reverse direction whereas kinesin tended to detach at patches of bound tau. Kinesin was inhibited at ~ 10-fold lower tau concentration than dynein and the microtubule-binding domain of tau was sufficient to inhibit motor activity. The differential modulation of dynein and kinesin motility suggests that MAPs can spatially regulate the balance of microtubule-dependent axonal transport.Active transport of cytoplasmic material along microtubules is critical for cell organization and function, and defects in this process are associated with dysfunction and disease (1). Much of the active transport in cells depends on the molecular motor proteins cytoplasmic dynein and kinesin-1, which transport cargo toward the minus-end (toward the cell center) and plusend of microtubules (toward the cell periphery), respectively. Dynein and kinesin have very different structures and translocation mechanisms (2). Kinesin has a compact motor domain and walks unidirectionally along single protofilaments with 8-nm steps (2). In contrast, dynein has a larger, more complex motor domain and is capable of variable step sizes, lateral steps across the microtubule surface, and processive runs toward both the minus-and plus-end of the microtubule (3-5). Cytoplasmic dynein function in vivo also requires an accessory complex, dynactin. This large, multiprotein complex is thought to facilitate dynein processivity (6) and may also regulate dynein activity (5). Within the cell, the balance between oppositely directed transport determines the steady-state distribution of organelles and biomolecules.In the crowded cell environment, dynein and kinesin compete with non-motile microtubuleassociated proteins (MAPs) for binding to the microtubule surface. MAPs bound to microtubules might also block the path of motor proteins. Thus, MAPs can provide spatiotemporal regulation of motor proteins in vivo. Tau, a neuronal MAP, inhibits kinesin activity in vivo and in vitro (7-10); however, its effect on dynein activity is not well understood. Our aim was to directly observe individual encounters between single dynein or kinesin motors and tau on microtubule tracks to determine how structurally distinct motors respond to obstacles in their path. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptTau is expressed in neurons as multiple splice forms in a developmentally regulated manner (11). These isoforms differ in the number of microtubule binding repeats and the length of the projection domain (Fig. 1A). Here we focused on the shortest and longest tau isoforms, tau23 and tau40, to comp...

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